1. Technical Field
The present invention relates generally to assays for the detection of Xenotropic Murine Leukemia Virus-related Retrovirus (“XMRV”) and diseases associated with XMRV infection. Additionally, the invention relates to specific XMRV antigens capable of inducing an immunogenic response as well as XMRV-related nucleic acids having significant diagnostic, screening, and therapeutic utilities.
2. Background Information
XMRV is a newly identified gammaretrovirus discovered in prostate cancer tissue using Virochip DNA microarray technology (A. Urisman et al., PloS Pathog. 2:e25, 2006; International Application No. PCT/US2006/013167). Using PCR-cloned cDNAs full-length genomic sequences were generated from several prostate tumors (A. Urisman et al., PloS Pathog. 2:e25, 2006). Analysis revealed a potentially replication-competent retrovirus most closely related to xenotropic murine leukemia viruses. Initial screening using a nested reverse transcription-PCR (RT-PCR) assay found that XMRV was detectable in 40% (8/20) of tumor tissues from prostate cancer patients homozygous for the reduced activity R462Q variant of RNase L, as compared to just 1.5% (1/66) of patients heterozygous (RQ) or homozygous wild-type (RR) for this allele (A. Urisman et al., PloS Pathog. 2:e25, 2006). Consistent with this observation, XMRV was detected in only 1 of 105 non-familial prostate cancer patients and 1 of 70 tissue samples from men without prostate cancer (N. Fischer et al., J. Clin. Virol. 43:277, 2008).
Subsequent studies by Dong et al. (Proc. Nat'l Acad. Sci. USA 104:1655, 2007), revealed several important insights regarding XMRV: (1) infectious virus was produced from prostate cancer cell lines transfected with an XMRV genome derived from 2 cDNA clones. Moreover, the virus replicated in both prostate and non-prostate cell lines; (2) XMRV replication in the prostate cancer-derived cell line, DU145, is interferon sensitive; and (3) the human cell surface receptor required for infection with XMRV is xenotropic and polytropic retrovirus receptor 1 (“Xpr1”). Finally, characterization of integration sites in human prostate DNA provided unequivocal evidence for the capacity of XMRV to infect humans (Dong et al., Proc. Nat'l Acad. Sci. USA 104:1655, 2007; Kim et al., J. Viral. 82:9964, 2008). More recently, XMRV was identified in patients with chronic fatigue syndrome (Lombardi et al., Science 326:585-589, 2009; Oct. 23, 2009).
An alternative to detecting or screening for the virus directly is to detect or screen for an indirect or surrogate marker such as antibodies elicited due to infection with XMRV. Immunoassays designed to detect specific antibodies to other viruses are known and offer several advantages: (1) bodily fluids (e.g., plasma, serum, cerebrospinal fluid, saliva, tears, urine, or aqueous extracts of tissues and cells), generally more accessible than, for example, prostate tissue, can be screened; (2) immunoassays are amenable to automation facilitating high-throughput screening; (3) antibodies are intrinsically relatively stable so are amenable for storage and testing; (4) titers of antibodies induced by infection with XMRV may persist longer than XMRV polypeptides in the compartments being measured; and (5) would provide a method to distinguish between recent and chronic infections based on antibody isotype present in the sample. Availability of a high throughput serological assay (immunoassay) that detects XMRV-specific antibodies elicited by infection with the virus in bodily fluids (e.g., plasma, serum, cerebrospinal fluid, saliva, tears, urine, or aqueous extracts of tissues and cells) would thus greatly facilitate studies to establish the etiologic role of XMRV in prostate cancer or other diseases.
All patents and publications referred to herein are hereby incorporated in their entirety by reference.